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Regenerative Endodontics-Potential Approaches in Revitalizing the Tooth Pulp

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Aggarwal A et al. Regenerative Endodontics.

Journal of Advanced Medical and Dental Sciences Research

@Society of Scientific Research and Studies

Journal home page: www.jamdsr.com doi: 10.21276/jamdsr ICV 2018= 82.06 UGC approved journal no. 63854

(e) ISSN Online: 2321-9599; (p) ISSN Print: 2348-6805

Review Article
Regenerative Endodontics- Potential Approaches in Revitalizing the Tooth Pulp -
A Review Article
Aayushi Aggarwal1, Vinisha Pandey2, Neetu Bansal3
1
BDS Student, 3Senior Lecturer, Department of Conservative Dentistry and Endodontics, Institute Of Dental Studies and
Technologies, Kadrabad, Modinagar, U.P., India;
2
Associate Professor, Department Of Conservative Dentistry And Endodontics, Maharana Pratap Dental College, Kanpur,
U.P., India

ABSTRACT:
When the maintenance of tooth in vital condition is no longer possible, the conventional treatment philosophy advocates the endodontic
treatment to retain it in a functional state. A paradigm shift of this thinking manifested with revascularization/regenerative procedures.
Regenerative endodontics is the creation and delivery of tissues to replace diseased, missing, and traumatized pulp. This review provides
an overview of regenerative endodontics and possible techniques that will allow regenerative endodontics to become a reality. These
potential techniques include root- canal revascularization, postnatal (adult) stem cell therapy, pulp implant, scaffold implant, three-
dimensional cell printing, injectable scaffolds, and gene therapy. These regenerative endodontic techniques will possibly involve some
combination of disinfection of infected root canal systems with apical enlargement to permit revascularization and use of stem cells,
scaffolds, and growth factors. Although the challenges of introducing endodontic tissue engineering therapies are substantial, the
potential advantages to patients and the profession are equally ground breaking. Patient demand is staggering both in scope and expense,
because tissue engineering therapy offers the chance of restoring natural function instead of surgical placement of an artificial prosthesis.
Key words: Regenerative endodontics, revascularization, pulp stem cells, tissue engineering, scaffolds, growth factors.

Received: 20 August, 2019 Revised: 28 August, 2019 Accepted: 29 September, 2019

Corresponding author: Dr. Vinisha Pandey, Associate Professor, Department Of Conservative Dentistry And
Endodontics, Maharana Pratap Dental College, Kanpur, U.P., India

This article may be cited as: Aggarwal A, Pandey V, Bansal N. Regenerative Endodontics- Potential Approaches in
Revitalizing the Tooth Pulp - A Review Article. J Adv Med Dent Scie Res 2019;7(10): 27-32.

INTRODUCTION
“Regenerative endodontics” is a branch of regenerative
medicine and has been defined as biological procedures
designed to replace damaged, diseased, or missing dental
structures, including dentine and root as well as cells of the
pulp-dentin complex, with living, viable tissues, preferably
of the same origin, that restore the normal physiological
functions of the pulp-dentin complex.[1] Regenerative
dental procedures have a long history, originating around
1952, when Dr. B. W. Hermann reported on the application
of Ca(OH)2 in a case report of vital pulp amputation.[2]
The goals of regenerative endodontics procedures are:
Primary goal: Elimination of symptoms & evidences of
bony healing.
Secondary goal: Elimination root wall thickness &/or
increased root length.
Tertiary goal: Positive response to vitality testing.[3]
The concept of the endodontic therapy has started with the
idea of retrieving the vitality of dental pulp as a potential
treatment option. It focuses on substituting injured and
diseased pulp with functional pulp tissue with the use of
biologically based procedures which restores the normal
function of pulp-dentin structure. Though the outcomes are
difficult to predict, deposition of hard tissue and continued
root development are expected to occur under ideal
conditions after this treatment. By providing an overview

Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019 27
Aggarwal A et al. Regenerative Endodontics.
of the methodological issues required to develop potential
regenerative endodontic therapies, we hope to present a call
for action to develop these approaches for clinical use.
Counterarguments
The counter argument to the development of regenerative
endodontic procedures is that the pulp in a fully developed
tooth plays no major role in form, function, or esthetics, and
thus its replacement by a filling material in conventional
root canal therapy is the most practical treatment but in
terms of esthetics, there is a potential risk that endodontic
filling materials and sealers may discolor the tooth crown.
In addition, it has been retrospected that endodontically
treated human teeth found the long-term intracanal
placement of calcium hydroxide may reduce the fracture
resistance of root dentin. It has also been noted that
although root canal therapy prolonged tooth survival, the
removal of pulp in a compromised tooth may still lead to
tooth loss in comparison with teeth with normal tissues. On
the other hand, although the replacement pulp has the
potential to revitalize teeth, it may also become susceptible
to further pulp disease and may require retreatment. The
implantation of engineered tissues also requires enhanced
microbiological control methods required for adequate
tissue regeneration.[4]
Tissue engineering
The concept of tissue engineering was introduced by
Charles Vacanti & Robert Langer[5] that applies principles
of engineering and life sciences towards development of
biological substitutes that restore, maintain or improve
tissue function. MacArthur and Oreffo[6] defined tissue
engineering as “understanding the principles of tissue
growth, and applying this to produce functional
replacement tissue for clinical use.” The principles of
regenerative medicine can be applied to endodontic tissue
engineering. Regenerative endodontics comprises research
in adult stem cells, growth factors, organ- tissue culture,
and tissue engineering materials.[4] [Fig.1]
Stem Growth
cells factors
Regenerative
Cell, tissue and organ culture Tissue
Figure 1. Regenerative endodontic procedures comprises
research in stem cells, growth factors, organ, tissue
culture and tissue engineering materials.
Stem cells
Stem cells are the ones that continuously divide and
produce progeny cells and can differentiate into various
Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019
other types of cells or tissues. [7] They can be pluripotent or
multipotent in nature and are located in specialized regions
within tissue termed as stem cell niches.[3] Niches are
variable, containing different cell types depending on the
need of its environment. The niche may be thought of as an
anchor for a particular stem cell that generates extrinsic
factors that control stem cell numbers and their fate.[1]
Oral stem cells come under the post-natal stem cell
category & includes: Dental pulp stem cells (DPSCs), Stem
cells of apical papilla SCAP), Inflammatory periapical
progenitor cells (iPAPCs), Periodontal ligament stem cells
(PDLSCs), Stem cells from human exfoliated deciduous
teeth (SHED), Dental follicle stem cells (DFSCs)[7] These
cells have the capability of differentiating into odontoblast-
like cells facilitating a progressive repopulation of the
radicular pulp space, promoting organized tissue repair,
angiogenesis & reinnervation.[3]
Growth factors:
Growth factors are extracellularly secreted proteins/signals
that bind two receptors on the cell signals
morphogenesis/organogenesis during epithelial-
mesenchymal interactions. They regulate the specialization
of stem cells to the desirable cell type & mediates key
cellular events in tissue regeneration including cell
proliferation, differentiation chemotaxis & matrix
synthesis[7] Currently, a variety of growth factors have been
identified with specific functions that can be used as a part
of stem cell & tissue engineering therapies.[4] Common
growth factors are bone morphogenic proteins (BMP),
fibroblast growth factor I or II(FGF), insulin like growth
factor I or II, colony stimulating growth factor (CSF),
epidermal growth factor (EGF), interleukin IL-1, IL- 13,
transforming growth factor α, β(TGF α & β), vascular
endothelial growth factor (VEGF), platelet-derived growth
factor (TGDF) & nerve growth factor (NGF).[7]
SCAFFOLD:
Scaffold is a three dimensional structure that contains
growth factors. It perform functions like it supports cell
organization & vascularization, aids stem cell proliferation
& differentiation, leads to improved & faster tissue
development, contains nutrients to promote cell survival &
growth, may contains antibiotics to prevent bacterial in
growth in the canal systems, also show some mechanical &
biological functions.[8]
Classification of Scaffolds
(I) Natural: collagen, platelet-rich plasma, fibrin and
GAGs
(II) Synthetic: polylactic acid, polyglcolic acid(PGA), and
poly (lactic-co-glycolic) acid (PLGA).
Natural polymers offer good biocompatibility and
bioactivity while synthetic polyers elaborate
physiochemical features such as dehydration rate,
28
Aggarwal A et al. Regenerative Endodontics.
microscopic and mechanical strength.[3] The choice of a
scaffold is critical in tissue regeneration. Most scaffolds are
organic in nature and used to provide surfaces on which
cells may adhere, grow, and organize. Scaffolds chosen for
laboratory studies are diverse, including natural or
synthetic polymers, extracellular matrices (EMCs), self-
assembling systems, hydrogels, and bioactive ceramics.
Recently, a synthetic polymer polycaprolactone was
successful in growing increasing numbers of stem cells
from apical papilla stem cells with apparent identification
of NOTCH signaling expression. The use of a self-
assembling peptide system that allows a “bottom-up”
approach of generating EMC materials, offering high
control at the molecular level, will be a major step forward
in constructing future scaffolds.[1] Scaffold-based
approaches have the potential for rapid formation of a
functional tooth of the correct shape and in the desired
location but it has to overcome challenges associated with
attachment to the jaw, infection, repetitive movement, and
ability to withstand load during maturation.[8]
Regenerative procedural approach in Endodontics
1. Root canal revascularization via blood clotting:
Iwaya and associates[9] were the first to coin the term
“revascularization” in their endodontic treatment of an
immature permanent tooth with apical periodontitis and a
sinus tract.[10] Revascularization of pulp can be defined as
growth of undifferentiated stems cells of periapical region
into the empty sterile/disinfected root canal space.[7]
The possible mechanisms by which revascularization
takes place are as follows:
A few vial pulp cells remaining the apical end of root canal
might proliferate into the newly formed matrix and
differentiate into odontoblasts. This may happen under
the influence of cells of HERS which are quite resistant to
destruction, even in the presence of inflammation.
Atubular dentin is laid down by odontoblasts at the apical
end of canal and on the lateral aspects of dentinal walls of
root canal. This leads to apexogenesis and reinforcing and
strengthening of root respectively.
Continues root development could be due to multipotent
dental stem cells, which are present abundantly in the
immature permanent teeth. These cells from apical end
might be seeded on to the existing dentinal walls and
might differentiate into odontoblasts and deposit tertiary or
atubular dentin. Stem cells in the periodontal ligament
can proliferate and grow into apical end and within the
root canal. They may deposit hard tissue both at the apical
end and on the lateral root walls. The evidence in support
of this hypothesis is presented by documentation of
cementum and sharpey’s fibers in the newly formed
tissues. The fourth possible mechanism of root
development could be attributed to SCAP or to the bone
marrow. Instrumentation beyond the confines of the root
canal to induce bleeding can also transplant mesenchymal
stem cells from the bone into the canal lumen. These cells
Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019
have extensive proliferating capacity.[3] An important
aspect of these cases is the use of intracanal irrigants
(NaOCl and chlorhexdine) with placement of antibiotics
(e.g. a mixture of ciprofloxacin, metronidazole, and
minocycline paste) for several weeks. This particular
combination of antibiotics effectively disinfects root canal
systems and increases revascularization of avulsed and
necrotic teeth, suggesting that this is a critical step in
revascularization.[4]
Size of apical foramen:
The size of apical foramen appears to be a major concern
in the regenerative endodontic therapy. It was suggested
that an apical foramen of atleast 1.1 mm in diameter was
necessary to promote vascularization and to maintain
initial cell viability via nutrient diffusion.[10]
Advantages:
Foremost, this approach is technically simple and can be
completed using currently available instruments and
medicaments without expensive biotechnology.
Subsequently, the regeneration of tissue in root canal
systems by a patient’s own blood cells avoids the
possibility of immune rejection and pathogen
transmission from replacing the pulp with a tissue
engineered construct. Plasma-derived fibrin clots are
being used for development as scaffolds as a useful aspect
of this approach.
Limitations:
However, there is a critical limitation to a blood clot
revascularization approach, because tissue engineering is
found on the delivery of effective concentrations and
compositions of cells to restore function; it is possible that
variations in cell concentration and composition,
particularly in older patients (where circulating stem cell
concentrations may be lower) may lead to variations in
treatment outcome.[4]
2. Postnatal stem cell therapy
This method involves placement of postnatal stem cells
into the disinfected root canal for regeneration of lost
dental tissue. The first postnatal stem cell therapy in
medicine was done for the treatment of severe combined
immune deficiency. Postnatal stem cells may be sourced
from umbilical cord blood, peripheral blood, bone
marrow, body fat, and other body tissues, like the pulp
tissue of teeth. The drawbacks of postnatal stem cell
therapy include low survival rates of injected cells,
minimal chance of cells to migrate to different parts
within the body, which may lead to aberrant patterns of
mineralization and difficulty in isolating the cells.[7]
3. Pulp Implantation
This concept seeks to renovate the two dimensional cell
cultures to a three-dimensional structure by growing the
cells in biodegradable membrane filters. Bohl et al., [11]
reported the formation of tissue with high cell density
29
Aggarwal A et al. Regenerative Endodontics.
similar to the natural pulp when pulp cells are cultured in
vitro on polyglycolic acid (PGA). Buurma et al.,[12]
observed extracellular matrix to be expressed in
immunecompromised mice when PGA was seeded with
pulp cells and implanted into subcutaneous spaces.
Angiogenesis occurred through PGA implants after three
weeks of implantation. The pulp stem cells must be
organized in such a way that it should support cell
organization and vascularization. Growing dental pulp
cells on collagen matrix was not successful and matrices
like vitronectin and laminin require further investigation.
The advantage of this philosophy is the ease of growing
cells on filters within the laboratory and their existence as
collective sheets which are a more stable than
unconnected cells and can be easily injected into empty
disinfected root canal systems. However, the drawback of
this technique is that there is a need for specialized
procedures to ensure proper adherence of cells to root canal
walls and handling fragile filters.[7]
4. Scaffold Implantation
Pulp stem cells may be ordered into a three dimensional
arrangement that can sustain cell organization and
vascularization. This can be consummate using a porous
polymer scaffold which is seeded with pulp stem cells. A
scaffold should contain growth factors that aid
proliferation and differentiation of stem cells, leading to
enhanced and more rapid tissue development. The
scaffolds that are used for this procedure are either
synthetic or natural. Synthetic scaffolds include polyester
materials like polycaprolactone (PCL), polyglycolic acid
(PGA) and polylactic acid (PLA). Natural scaffolds may
be collagen, chitosan, fibrin or glycosamino glycans.
Dentin chips have been reported to stimulate reparative
dentin bridge formation in teeth with exposed pulp.
Dentin chips will be a reservoir of growth factors thereby
acting as a matrix for pulp stem cell attachment.[7]
5. Injectable Scaffold Delivery
Rigid tissue engineered scaffold structures provide
excellent support for cells used in bone and other body
areas where the engineered tissue is required to provide
physical support. However, in root canal systems a tissue
engineered pulp is not required to provide structural
support of the tooth. This will allow tissue engineered
pulp tissue to be administered in a soft three-dimensional
scaffold matrix, such as a polymer hydrogel. Hydrogels
are injectable scaffolds that can be delivered by syringe.
Hydrogels have the potential to be noninvasive and easy
to deliver into root canal systems. In theory, the hydrogel
may promote pulp regeneration by providing a substrate
for cell proliferation and differentiation into an organized
tissue structure.[4]
6. Three-Dimensional Cell Printing
In theory, an ink-jet-like device is used to dispense layers
Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019
of cells suspended in a hydrogel to recreate the structure
of the tooth pulp tissue. The three-dimensional cell
printing technique can be used to precisely position cells,
and this method has the potential to create tissue
constructs that mimic the natural tooth pulp tissue
structure. The ideal positioning of cells in a tissue
engineering construct would include placing into cleaned
odontoblastoid cells around the periphery to maintain and
repair dentin, with fibroblasts in the pulp core supporting
a network of vascular and nerve cells. However there is a
disadvantage of using the three-dimensional cell printing
technique theoretically that careful orientation of the pulp
tissue construct according to its apical and coronal
asymmetry would be required during placement and
shaped root canal systems. However, early research has
yet to show that three-dimensional cell printing can create
functional tissue in vivo.[4]
Gene therapy
Gene therapy is a relatively new field in regenerative
endodontics where preliminary attempts focuses on
delivering genes that are capable of matrix formation and
mineralization into pulp space to promote tissue repair
using vectors. Its practicality, potential health hazards and
ethical concerns are much demanding, which accounts to
the limited exploration of the technique in endodontics.
Once successful, this technique could be a landmark
development in the field of regenerative endodontics.[4]
[Table-1]
Challenges in regenerative endodontics
A. Disinfection of root canal and discolouration of
crown:
One of the biggest challenges encountered in endodontics
is inadequate disinfection of infected root canals. NaOCl
is the most widely recommended irrigant (concentration ≤
1.5%) . 17 % EDTA is another chemical agent that is
recommended in regeneration procedure as it helps in the
dissolution and release of impregnated growth factors in
root dentin during dentinogenesis. These growth factors
enhance the stem cell survival and its proliferation. EDTA
is also useful in reversing the detrimental effect of high
concentration of NaOCl. Regarding intracanal
medicaments, Triple Antibiotic Paste (TAP) is difficult to
remove from the root canal and causes discoloration of
the crown portion over a period of time due to presence
of minocycline in it that binds with calcium of dentin
forming insoluble complexes.[7] To avoid staining while
using TAP, the pulp chamber should be sealed with dentin
bonding agent and ensure that TAP remains below CEJ.
Besides this, Calcium hydroxide also has deleterious
effect like weakening the root dentin, with a potential for
fracture.[4]
30
Aggarwal A et al. Regenerative Endodontics.

Table1: Summarized table for regenerative procedural approaches in endodontics

Technique name Procedure Figure
Root canal revascularization Open up tooth apex to 1mm to allow bleeding into
root canals

Stem cell therapy Autologous or allogenic stem cells are delivered to

tooth via injectable matrix

Pulp implantation Pulp tissue is grown n the laboratory in sheets and

implanted surgically

Scaffold implantation Pulp cells are seeded onto a 3-D scaffold made of
polymers and surgically implanted

3-D cell printing Ink-jet like device dispenses layers of cells in a

hydrogel which is surgically implanted.

Injectable scaffolds Polymerizable hydrogels, alone or containing cell

suspension are delivered by injection

Gene therapy Mineralizing genes are transfected into vital pulp

cells of necrotic and symptomatic teeth.

Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019 31
 Aggarwal A et al. Regenerative Endodontics.
A. Removal of smear layer
Even though there is minimal instrumentation of the root
canal in regenerative procedure, there is limited smear
layer formation. This prevents stem cells from adhering
on to root canal walls, contributing to failure of treatment.
A 17% solution of EDTA as final rinse in the root canal
will aid in removal of smear layer as well as enhance the
attachment of the stem cells by providing a better surface
on the root dentin for their survival. Other chemicals used
for this purpose are doxycycline, citric acid and MTAD.[7]
B. Developing an ordered functional pulp tissue
Developing a functional tissue is still a problem in
regeneration. Despite best efforts to recreate lost tissue,
the type of tissue is still unknown. The development of the
normal harmony and spatial arrangement of dentin pulp
complex is still in research. The 3D cell printing will be a
possible solution in the near future, but the problem with
this technology is the difficulty in exact placement and
positioning inside root canal. Only by achieving such a
balanced spatial oriented cell lineage in the root canal
through regeneration can this method be deemed
successful.[7]
C. Appropriate coronal seal
A leakage-free coronal restoration is mandatory in
regenerative endodontics as well as in subsequent
restorative procedures. The material that provides such
seal should be biocompatible, have to maintain cell
viability of the regenerated pulp, should minimize
microleakage and provide adequate adhesion to the
overlaying restorative material. The materials under
consideration are calcium silicate based cements like
mineral trioxide aggregate (MTA) and biodentine.[7]
Future prospective
Regenerative endodontic strategies are continuously being
updated and improved to benefit dentistry in every possible
way. American Association of Endodontists Foundation
has recently awarded a grant of $1.7 million[13] to evaluate
the effectiveness of two regenerative approaches
(REGENDO and REVASC) compared with the
conventional MTA apexification. The trial will be carried
out in collaboration with Loma Linda University,
University of Texas Health Science Center at San Antonio
and the University of Maryland School Of Dentistry and is
estimated to complete in December 2019. Iohara et al.[14]
aims to use pulp stem cells with granulocyte-colony
stimulating factor (G-CSF) for pulp/dentin regeneration to
fully restore the tooth instead of filling, capping or
extracting it. Misako Nakashima (Japan) said that a clinical
trial of pulp regeneration has already been initiated with the
permission of the Japanese Ministry of Health, Labor and
Welfare. Recently, PRF box has been announced[15] to
produce homogenously thickened hydrated exudate rich in
platelets, vitronectin, leukocytes, and fibronectin expressed
from the fibrin clots that have improved the issues
Journal of Advanced Medical and Dental Sciences Research |Vol. 7|Issue 10| October 2019
View publication stats
regarding the handling of the platelet-rich fibrin (PRF) clot.
It is likely that the next advance in regenerative dentistry is
the availability of regenerative dental kits, which will
enable the dentists the ability to deliver regenerative
therapies locally as part of routine dental practice.[8]
Conclusion
Regenerative endodontics holds promise of restoring pulp-
dentin complex in teeth with immature roots and necrotic
pulps. This procedure has potential advantages versus
traditional treatment procedures of increasing root wall
thickness and root length while maintaining immune
competency. Still significant scientific hurdles need to be
overcome with continued growth in knowledge and
armamentarium.[3]
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3. Grossman, Regenerative endodontics In: Chandra B(ed.),
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4. Murray PE, Garcia-Godoy F, Hargreaves KM. Regenerative
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regenerative endodontics. J Conserv Dent 2015;18:1-6
9. Iwaya, S.I.; Ikawa, M.; Kubota, M. Revascularization of an
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13. Dental Tribune International jan 29, 2014. New regenerative
endodontics study receives almost $2 million.
14. Iohara K, Murakami M, Takeuchi N, Osako Y, Ito M,
Ishizaka R, et al. A novel combinatorial therapy with pulp
stem cells and granulocyte colony-stimulating factor for total
pulp regeneration. Stem Cells Transl Med 2013;2:521-33.
15. Khiste SV, Tari RN. Platelet-rich fibrin as a biofuel for tissue
regeneration. Biomaterials 2013.
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